K

Light chains present but uncharacterized Three light chain types present Light chains present but uncharacterized Light chains of teleost type k, other

Light chains present but uncharacterized

No 'classical immunoglobulin' but proteins cross-reactive with antibodies of shark and lampreys occur heavy chain containing one variable and six constant domains and may represent the primitive immunoglobulin in evolution. IgW variable domains resemble those of heavy chains, but are significantly different and show substantial variation in sequence consistent with the diversity to recognize a large number of antigens. Furthermore, major diversity both in isotypes and variable domain sequences has been found among light chains of cartilaginous fishes. The dominant family in carcharhine sharks (e.g. the sandbar shark) is a family related to the \ light chains of higher vertebrates, and this group itself consists of at least three major families containing more than two hundred separate genes. The dominant class of light chains in the nurse shark resembles mammalian k chain and that in the horned shark is a separate type which appears to be restricted to the sharks.

Origin of variable region diversity

Investigations of mammals, birds and the Xenopus have indicated that two genes are required early in the development of T and B cells in order for recombination of variable, diversity and joining segments of immunoglobulin light and heavy chains and T cell receptor chains to occur. These have been termed RAG-1 (recombination activating gene 1) and RAG-2 (recombination activating gene 2). Although their mechanism of action is currently unknown, their presence is required in early T and B cells to allow recombination. Genes unequivocally homologous to the human RAG-1 gene occur in all jawed vertebrates including sharks, paddlefish, goldfish, xenopus and the axolotl. Comparison of the sequence of the complete 1113 amino acid shark RAG product with the human gene product shows regions of greater than 85% identity as well as segments of approximately 20-50% identity. All RAG-1 genes have homology to DNA-processing enzymes, expressing among other features the so-called RING

finger Zn-finger motif expressed by the yeast excision repair enzyme RAD18. Analysis of the shark sequence indicates that RAG-1 genes are members of the integrase family of site-specific DNA-rearrange-ment enzymes that have been studied in bacteria. Comparable analyses of sequence homology suggests that the vertebrate RAG-2 molecule is homologous to integration host factors that in bacteria act in concert with the integrases.

Origins of immunoglobulins

The evidence is now conclusive that the most primitive living vertebrates, the cyclostomes hagfish and lampreys, make antibodies comparable to those of higher vertebrates in charge dispersity and in consisting of two types of polypeptide chains (light and heavy) that can associate covalently by disulfide bonds. These molecules are serologically cross-reactive with those of elasmobranchs, but their protein and gene structure remain elusive at this time. The question of the origin of the rearranging immunoglobulin system likewise is a challenging contemporary problem. It is likely that this system arose in the deuterostome ancestors of vertebrates. Consistent with this hypothesis, molecules found in some protochordate species (tunicates) are anti-genically related to heavy chains of sharks and lampreys and have sufficient mass (25-30 kDa) to contain the product of V and C gene segments. Whether these molecules prove to be the protoimmunoglobu-lin 'missing links' remains to be determined, but the search for the first vertebrate-type antibody continues to be a major issue in immunology.

See also: Amphibian immune system; Avian immune system; Fish immune system; Immunoglobulin genes; Immunoglobulin structure; MHC, evolution of; Ovine immune system; Phylogeny of the immune response; Porcine immune system; Rabbit immune

Table 3 Comparison of X light chain sequences of the sandbar shark (clone 5.1), mouse (MOPC 315), human (Meg) and chicken variable

Shark House Human Chicken

Shark House Human Chicken

Shark House Human Chicken

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